This invention relates to substituted aromatic tricyclic compounds containing nicotinonitrile rings as well as the pharmaceutically acceptable salts thereof. The compounds of the present invention inhibit the action of certain protein kinases, thereby inhibiting the abnormal growth of particular cell types. The compounds of this invention are therefore useful for the treatment or inhibition of certain diseases that are the result of deregulation of these protein kinases. The compounds of this invention are anti-cancer agents and are useful for the treatment or inhibition of cancer in mammals. In addition, the compounds of this invention are useful for the treatment and inhibition of polycystic kidney disease and colonic polyps.
Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine, or histidine residue located on a protein substrate. Protein kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins function as kinases and it is by this process that they effect signaling. The interaction of growth factors with these receptors is a necessary event in normal regulation of cell growth. However, under certain conditions, as a result of either mutation or over expression, these receptors can become deregulated; the result of which is uncontrolled cell proliferation which can lead to tumor growth and ultimately to the disease known as cancer [Wilks, A. F., Adv. Cancer Res., 60, 43 (1993) and Parsons, J. T.; Parsons, S. J., Important Advances in Oncology, DeVita, V. T. Ed., J. B. Lippincott Co., Phila., 3 (1993)]. Among the growth factor receptor kinases and their proto-oncogenes that have been identified and which are targets of the compounds of this invention are the epidermal growth factor receptor kinase (EGF-R kinase, the protein product of the erbB oncogene), and the product produced by the erbB-2 (also referred to as the neu or HER2) oncogene. Since the phosphorylation event is a necessary signal for cell division to occur and since overexpressed or mutated kinases have been associated with cancer, an inhibitor of this event, a protein tyrosine kinase inhibitor, will have therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. For example, over expression of the receptor kinase product of the erbB-2 oncogene has been associated with human breast and ovarian cancers [Slamon, D. J. et al., Science, 244, 707 (1989) and Science, 235, 177 (1987)]. Deregulation of EGF-R kinase has been associated with epidermoid tumors [Reiss, M., et al., Cancer Res., 51, 6254 (1991)], breast tumors [Macias, A. et al., Anticancer Res., 7, 459 (1987)], and tumors involving other major organs [Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)]. Because of the importance of the role played by deregulated receptor kinases in the pathogenesis of cancer, many recent studies have dealt with the development of specific PTK inhibitors as potential anti-cancer therapeutic agents [some recent reviews: Traxler, P., Exp. Opin. Ther. Patents, 8, 1599 (1998) and Bridges, A. J., Emerging Drugs, 3, 279 (1998)].
It is also known that deregulation of EGF receptors is a factor in the growth of epithelial cysts in the disease described as polycystic kidney disease [Du, J., Wilson, P. D., Amer. J. Physiol., 269 (2 Pt 1), 487 (1995); Nauta, J., et al., Pediatric Research, 37(6), 755 (1995); Gattone, V. H. et al., Developmental. Biology, 169(2), 504 (1995); Wilson, P. D. et al., Eur. J. Cell Biol., 61(1), 131, (1993)]. The compounds of this invention, which inhibit the catalytic function of the EGF receptors, are consequently useful for the treatment of this disease.
The mitogen-activated protein kinase (MAPK) pathway is a major pathway in the cellular signal transduction cascade from growth factors to the cell nucleus. The pathway involves kinases at two levels: MAP kinase kinases (MAPKK), and their substrates MAP kinases (MAPK). There are different isoforms in the MAP kinase family. (For review, see Seger, R.; Krebs, E. G., FASEB, 9, 726, (1995).) The compounds of this invention can inhibit the action of two of these kinases: MEK, a MAP kinase kinase, and its substrate ERK, a MAP kinase. MEK is activated by phosphorylation on two serine residues by upstream kinases such as members of the raf family. When activated, MEK catalyzes phosphorylation on a threonine and a tyrosine residue of ERK. The activated ERK then phosphorylates and activates transcription factors in the nucleus, such as fos and jun, or other cellular targets with PXT/SP sequences. ERK, a p42 MAPK, is found to be essential for cell proliferation and differentiation. Over-expression and/or over-activation of MEK or ERK has been found to be associated with various human cancers [For example, Sivaraman, V. S.; Wang, H-Y.; Nuovo, G. J. Malbon, C. C. J. Clin. Invest., 99, 1478 (1997)]. It has been demonstrated that inhibition of MEK prevents activation of ERK and subsequent activation of ERK substrates in cells, resulting in inhibition of cell growth stimulation and reversal of the phenotype of ras-transformed cells [Dudley, D. T.; Pang, L.; Decker, S. J.; Bridges, A. J.; Saltiel, A. R., Proc. Nat. Acad. Sci., 92, 7686, (1995)]. Since, as demonstrated below, the compounds of this invention can inhibit the coupled action of MEK and ERK, they are useful for the treatment of diseases such as cancer which are characterized by uncontrolled cell proliferation and which, at least in part, depend on the MAPK pathway.
As mentioned above, members of the raf family of kinases phosphorylate serine residues on MEK. There are three serine/threonine kinase members of the raf family known as a-raf, b-raf and c-raf. While mutations in the raf genes are rare in human cancers, c-raf is activated by the ras oncogene which is mutated in a wide number of human tumors. Therefore inhibition of the kinase activity of c-raf may provide a way to prevent ras mediated tumor growth [Campbell, S. L., Oncogene, 17, 1395 (1998)].
The Src family of cytoplasmic protein tyrosine kinases consists of at least eight members (Src, Fyn, Lyn, Yes, Lck, Fgr, lck and Bik) that participate in a variety of signaling pathways [Schwartzberg, P. L., Oncogene, 17, 1463–1468, (1998)]. The prototypical member of this tyrosine kinase family is p60scr (Src). Src is involved in proliferation and migration responses in many cell types. In limited studies, Src activity has been shown to be elevated in breast, colon (˜90%), pancreatic (>90%) and liver (>90%) tumors. Greatly increased Src activity is also associated with metastasis (>90%) and poor prognosis. Antisense Src message impedes growth of colon tumor cells in nude mice [Staley et al., Cell Growth & Differentiation., 8, 269–74, (1997)], suggesting that Src inhibitors should slow tumor growth. In addition to its role in cell proliferation, Src also acts in stress response pathways, including the hypoxia response, and nude mice studies with colon tumor cells expressing antisense Src message have reduced vascularization [Ellis, et al., J. Biol. Chem., 273, 1052–7 (1998)], which suggests that Src inhibitors would be anti-angiogenic as well as anti-proliferative.
In addition to its role in cancer, Src also appears to play a role in osteoporosis. Mice genetically engineered to be deficient in src production were found to exhibit osteopetrosis, the failure to resorb bone [Soriano, P., Cell, 64, 693 (1991); Boyce, B. F., J. Clin., Invest., 90, 1622 (1992)]. This defect was characterized by a lack of osteoclast activity. Since osteoclasts normally express high levels of Src, inhibition of Src kinase activity may be useful in the treatment of osteoporosis [Missbach, M., Bone, 24, 437 (1999)].
In addition to EGFr, there are several other RTKs including FGFr, the receptor for fibroblast growth factor (FGF); flk-1, also known as KDR, and flt-1, the receptors for vascular endothelial growth factor (VEGF); and PDGFr, the receptor for platelet derived growth factor (PDGF). The formation of new blood vessels, a process known as angiogenesis, is essential for tumor growth. Two natural angiogenesis inhibitors, angiostatin and endostatin, dramatically inhibited the growth of a variety of solid tumors. [O'Reilly, M. S., Cell, 79, 315 (1994); O'Reilly, M. S., Nature Medicine, 2, 689 (1996); O'Reilly, M. S., Cell, 88, 277 (1997)]. Since FGF and VEGF are known to stimulate angiogenesis, inhibition of the kinase activity of their receptors should block the angiogenic effects of these growth factors. In addition, the receptor tyrosine kinases tie-1 and tie-2 also play a key role in angiogenesis [Sato, T. N., Nature, 376, 70 (1995)]. Compounds of the invention that inhibit the kinase activity of FGFr, flk-1, flt-1, tie-1 or tie-2 may inhibit tumor growth by their effect on angiogenesis. Normal angiogenesis is required in many physiological conditions such as wound healing, female reproduction and fetal development. Abnormal or pathological angiogenesis has been implicated in neoplastic diseases including solid tumor growth, metastasis, and Karposi's sarcoma; various eye diseases including diabetic retinopathy, and macular degeneration; inflammatory conditions including rheumatoid arthritis, and osteoarthritis; skin diseases including psoriasis, eczema and scleroderma; as well as ulcerative colitis and childhood haemangiomas [Toi, M. et al., Breast Cancer Res. And Treat., 36, 192–204 (1995); Folkman, J., Nature Medicine, 1, 27–31 (1995); Jackson, J. R. et al., FASEB J., 11, 457–465 (1997)]. Inhibition of VEGF function has been shown to inhibit disease progression in tumors [Borgstrom, P. et al., Cancer Res., 56, 4032–4039 (1996); Kim, J. K. et al., Nature, 362, 841–844 (1993)] and retinal neovascularization [Aiello, L. P. et al., Proc. Nat. Acad. Sci., 92, 10457–10461 (1995)] as well as vascular dysfunction mediated by glucose in models of diabetes [Tilton, R. G. et al., J. Clin. Invest., 99, 2192–2202 (1997)].
PDGF is a potent growth factor and chemoattractant for smooth muscle cells (SMCs) and the renarrowing of coronary arteries following angioplasty is due in part to the enhanced proliferation of SMCs in response to increased levels of PDGF. Therefore, compounds that inhibit the kinase activity of PDGFr may be useful in the treatment of restenosis. In addition, since PDGF and PDGFr are overexpressed in several types of human gliomas, small molecules capable of suppressing PDGFr activity, have potential utility as anticancer therapeutics [Nister, M., J. Biol. Chem. 266, 16755 (1991); Strawn, L. M., J. Biol. Chem. 269, 21215 (1994)].
In accordance with the present invention, the tricyclic ring systems described herein will be numbered as indicated in the representative formulas below (where U=N or O or S):

No fully aromatic fused tricyclic compounds containing nicotinonitrile rings have been reported that have biological activity as inhibitors of protein tyrosine kinases. 3-Cyanoquinoline derivatives described in WO-9843960 have been disclosed as inhibitors of tyrosine kinase. A 3-cyanoquinoline with a 4-(2-methyl anilino) substituent having gastric (H+/K+)-ATPase inhibitory activity at high concentrations has been described [Ife R. J., et al., J. Med. Chem., 35(18), 3413 (1992)]. However, there are no references to any fully aromatic tricyclic compounds containing nicotinonitrile rings in the above publications.
In WO-9713760, a series of fused tricyclic compounds containing pyridine rings (and pyrimidines) that are reported to be inhibitors of protein tyrosine kinases is disclosed. However, it is specified that the position meta to the pyridine nitrogen bears a hydrogen atom only. No compounds possessing cyano substituents at this position are claimed. In two patents: AU 8767450 and U.S. Pat. No. 4,952,584, 4-amino-9H-pyrido-(2,3-b)-indole-3-carboxylic acid derivatives are disclosed as anxiolytic and antidepressant agents. No corresponding 3-cyano substituents are claimed. In EP 755934, fused tricyclic compounds containing nicotinonitrile rings are disclosed as endothelin receptor antagonists. However, these derivatives do not have the unique combination of substituents contained in the compounds of the present invention. In particular, it is specified that these compounds possess aromatic substituents directly attached to the position para to the pyridine nitrogen. Such substituents are not claimed in the present invention. Similarly, a series of compounds claimed in WO 9705137 do include tricyclics containing nicotinonitrile rings, but with hydrogen or simple alkyl chains attached to the position para to the pyridine nitrogen. Such substituents are not claimed in the present invention. Several patents exist which disclose substituted quinoline compounds as tyrosine kinase inhibitors, none of which possess the 3-cyano substituent: 1. An international patent WO-9813350 describing 3-fluoroquinoline and quinoline tyrosine kinase inhibitors. 2. WO-9609294 discloses inhibitors of protein tyrosine kinases that include 4-anilino quinolines with a large variety of substituents on positions 5–8 but which must also have a hydrogen atom at position 3. 3. U.S. Pat. No. 5,480,883 discloses quinoline derivatives that are inhibitors of protein tyrosine kinases but these derivatives do not have the unique combination of substituents, including the 3-cyano group, contained in the compounds of the present invention.
In addition to the above-mentioned compounds, certain tricyclics containing pyrimidine rings are known to be inhibitors of protein tyrosine kinases. WO-9749688, WO-9519970, U.S. Pat. No. 5,679,683 and the previously-mentioned WO-9713760 disclose a variety of tricyclic heterocycles which are tyrosine kinase inhibitors. Other patent applications WO-9802434, WO-9730044 and EP-837063 describe quinazolines substituted at positions 5 to 8 with one or more optionally substituted 5- or 6-membered heterocyclic rings.
In addition to the aforementioned patent applications, a number of publications describe fused tricyclics containing 4-anilinopyrimidine rings: Rewcastle G. W., et. al., J. Med. Chem., 39, 918 (1996); Bencteux, E., et. al., J. Heterocycl. Chem., 34, 1375, (1997); Palmer B. D., et. al. J. Med Chem., 40, 1519 (1997); and Zhou, H., et. al., Book of Abstracts, 210th ACS National Meeting, Chicago, Ill., August 20–24 (1995), Issue Pt. 2, MEDI-017. There are no publications that describe fused tricyclic tricyclic compounds containing nicotinonitrile rings as PTK inhibitors.
SUMMARY OF THE INVENTION
The present invention relates to certain protein kinase inhibitors of formula 1 having the structure:
wherein:    Ar is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atoms; or    Ar is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono-, di-, or tri-substituted with substituents selected from the group consisting of halogen, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, azido, hydroxyalkyl of 1–6 carbon atoms, halomethyl, alkoxymethyl of 2–7 carbon atoms, alkanoyloxymethyl of 2–7 carbon atoms, alkoxy of 1–6 carbon atoms, alkylthio of 1–6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2–7 carbon atoms, alkanoyl of 2–7 carbon atoms, benzoyl, amino, alkylamino of 1–6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1–6 carbon atoms, alkenoylamino of 3–8; carbon atoms, alkynoylamino of 3–8 carbon atoms, alkanoyloxy of 1–6 carbon atoms, alkenoyloxy of 3–8 carbon atoms, alkynoyloxy of 3–8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2–7 carbon atoms, N,N-dialkylcarbamoyl of 3–13 carbon atoms, carboxyalkyl of 2–7 carbon atoms, carboalkoxyalkyl of 3–8 carbon atoms, aminoalkyl of 1–5 carbon atoms, N-alkylaminoalkyl of 2–9 carbon atoms, N,N-dialkylaminoallyl of 3–10 carbon atoms, N-alkylaminoalkoxy of 3–9 carbon atoms, N,N-dialkylaminoalkoxy of 4–10 carbon atoms, mercapto, methylmercapto and benzoylamino; or    Ar is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms where the bicyclic heteroaryl ring may contain 1 to 4 heteroatoms selected from N, O, and S wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono- di-, tri, or tetra-substituted with substituent(s) independently selected from the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, azido, hydroxyalkyl of 1–6 carbon atoms, halomethyl, alkoxymethyl of 2–7 carbon atoms, alkanoyloxymethyl of 2–7 carbon atoms, alkoxy of 1–6 carbon atoms, alkylthio of 1–6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2–7 carbon atoms, alkanoyl of 2–7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1–6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1–6 carbon atoms, alkenoylamino of 3–8 carbon atoms, alkynoylamino of 3–8 carbon atoms, carboxyalkyl of 2–7 carbon atoms, carboalkoxyalkyl of 3–8 carbon atoms, aminoalkyl of 1–5 carbon atoms, N-alkylaminoalkyl of 2–9 carbon atoms, N,N-dialkylaminoalkyl of 3–10 carbon atoms, N-alkylaminoalkoxy of 3–9 carbon atoms, N,N-dialkylaminoalkoxy of 4–10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1–6 carbon atoms, alkenoyloxy of 3–8 carbon atoms, alkynoyloxy of 3–8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2–7 carbon atoms, N,N-dialkylcarbamoyl of 3–13 carbon atoms, and benzoylamino; or    Ar is the radical:
    A′ is a pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- or di-substituted with a substituent(s) independently selected from the group consisting of alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, azido, hydroxyalkyl of 1–6 carbon atoms, halogen, halomethyl, alkoxymethyl of 2–7 carbon atoms, alkanoyloxymethyl of 2–7 carbon atoms, alkoxy of 1–6 carbon atoms, alkylthio of 1–6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2–7 carbon atoms, alkanoyl of 2–7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1–6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1–6 carbon atoms, alkenoylamino of 3–8 carbon atoms, alkynoylamino of 3–8 carbon atoms, carboxyalkyl of 2–7 carbon atoms, carboalkoxyalkyl of 3–8 carbon atoms, aminoalkyl of 1–5 carbon atoms, N-alkylaminoalkyl of 2–9 carbon atoms, N,N-dialkylaminoalkyl of 3–10 carbon atoms, N-alkylaminoalkoxy of 3–9 carbon atoms, N,N-dialkylaminoalkoxy of 4–10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1–6 carbon atoms, alkenoyloxy of 3–8 carbon atoms, alkynoyloxy of 3–8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2–7 carbon atoms, N,N-dialkylcarbamoyl of 3–13 carbon atoms, and benzoylamino;    T is substituted on A′ at carbon and is —NH(CH2)m—, —O(CH2)m—, —S(CH2)m—, —NR(CH2)m—, —(CH2)m—, —(CH2)mNH—, —(CH2)mO—, —(CH2)mS—, —SO(CH2)m—, —SO2(CH2)m—, —CO(CH2)m—, —(CH2)mCO—, —(CH2)mSO—, —(CH2)mSO2— or —(CH2)mNR—;    L is a phenyl ring that is optionally substituted with one, two, or three substituent(s) independently selected from the group consisting of alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, azido, hydroxyalkyl of 1–6 carbon atoms, halogen, halomethyl, alkoxymethyl of 2–7 carbon atoms, alkanoyloxymethyl of 2–7 carbon atoms, alkoxy of 1–6 carbon atoms, alkylthio of 1–6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2–7 carbon atoms, alkanoyl of 2–7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1–6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1–6 carbon atoms, alkenoylamino of 3–8 carbon atoms, alkynoylamino of 3–8 carbon atoms, carboxyalkyl of 2–7 carbon atoms, carboalkoxyalkyl of 3–8 carbon atoms, aminoalkyl of 1–5 carbon atoms, N-alkylaminoalkyl of 2–9 carbon atoms, N,N-dialkylaminoalkyl of 3–10 carbon atoms, N-alkylaminoalkoxy of 3–9 carbon atoms, N,N-dialkylaminoalkoxy of 4–10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1–6 carbon atoms, alkenoyloxy of 3–8 carbon atoms, alkynoyloxy of 3–8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2–7 carbon atoms, N,N-dialkylcarbamoyl of 3–13 carbon atoms, and benzoylamino; or    L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S and where the heteroaryl ring may be optionally mono- or di-substituted with substituent(s) selected from the group consisting of halogen, oxo, thiocarbonyl, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, azido, hydroxyalkyl of 1–6 carbon atoms, halomethyl, alkoxymethyl of 2–7 carbon atoms, alkanoyloxymethyl of 2–7 carbon atoms, alkoxy of 1–6 carbon atoms, alkylthio of 1–6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2–7 carbon atoms, alkanoyl of 2–7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1–6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1–6 carbon atoms, alkenoylamino of 3–8 carbon atoms, alkynoylamino of 3–8 carbon atoms, carboxyalkyl of 2–7 carbon atoms, carboalkoxyalkyl of 3–8 carbon atoms, aminoalkyl of 1–5 carbon atoms, N-alkylaminoalkyl of 2–9 carbon atoms, N,N-dialkylaminoalkyl of 3–10 carbon atoms, N-alkylaminoalkoxy of 3–9 carbon atoms, N,N-dialkylaminoalkoxy of 4–10 carbon atoms, mercapto, methylmercapto, alkanoyloxy of 1–6 carbon atoms, alkenoyloxy of 3–8 carbon atoms, alkynoyloxy of 3–8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2–7 carbon atoms, N,N-dialkylcarbamoyl of 3–13 carbon atoms, and benzoylamino;    m is 0–3;    n is 0–1;    X is NH O, S, or NR;    R is alkyl of 1–6 carbon atoms;    Y and Z are both carbon or N; the ring structure of formula 1 then being a fused 5,6,6 or 6,6,6 tricycle; or one of Y and Z is N, O or S, and the other is a bond between the two end rings; the ring structure of formula 1 then being a fused 5,5,6 or 6,5,6 tricycle; or one of Y or Z is N with the other being carbon; the ring structure of formula 1 then being a fused 5,6,6 or 6,6,6 tricycle;
    A and D are each, independently, carbon, N, O, or S;    B is carbon or N;    the dashed line indicates an optional double bond;    R1, R2, R3, and R4 are each, independently, not present, hydrogen, halogen, hydroxy, amino, hydroxyamino, trifluoromethyl, trifluoromethoxy, mercapto, alkyl of 1–6 carbon atoms, cycloalkyl of 3–8 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, alkenyloxy of 2–6 carbon atoms, alkynyloxy of 2–6 carbon atoms, hydroxyalkyl of 1–6 carbon atoms, mercaptoalkyl of 1–6 carbon atoms, halomethyl, alkoxymethyl of 2–7 carbon atoms, alkoxy of 1–6 carbon atoms, cycloalkoxy of 3–8 carbon atoms, alkylthio of 1–6 carbon atoms, cycloalkylthio of 3–8 carbon atoms, alkylsulphinyl of 1–6 carbon atoms, alkylsulfonyl of 1–6 carbon atoms, alkylsulfonamido of 1–6 carbon atoms, alkenylsulfonamido of 2–6 carbon atoms, alkynylsulfonamido of 2–6 carbon atoms, cyano, nitro, carboxy, alkoxycarbonyl of 2–7 carbon atoms, alkanoyl of 2–7 carbon atoms, alkenoyl of 3–7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6–12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of 1–6 carbon atoms, alkanoyloxy of 2–7 carbon atoms, alkenoyloxy of 3–8 carbon atoms, alkynoyloxy of 3–8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2–7 carbon atoms, N,N-dialkylcarbamoyl of 3–13 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoyloxymethyl group of 2–7 carbon atoms, alkenoyloxymethyl group of 2–7 carbon atoms, alkynoyloxymethyl group of 2–7 carbon atoms, azido, benzoyl, carboxyalkyl of 2–7 carbons, carboalkoxyalkyl of 3–8 carbon atoms,
    R5 is independently hydrogen, alkyl of 1–6 carbon atoms, aminoalkyl of 1–6 carbon atoms, N-alkylaminoalkyl of 2–9 carbon atoms, N,N-dialkylaminoalkyl of 3–12 carbon atoms, N-cycloalkylaminoalkyl of 4–12 carbon atoms, N-cycloalkyl-N-alkylaminoalkyl of 5–18 carbon atoms, N,N-dicycloalkylaminoalkyl of 7–18 carbon atoms, morpholino-N-alkyl wherein the alkyl group is 1–6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1–6 carbon atoms, N-alkyl-piperazino-N-alkyl wherein either alkyl group is 1–6 carbon atoms, azacycloalkyl-N-alkyl of 3–11 carbon atoms, hydroxyalkyl of 1–6 carbon atoms, alkoxyalkyl of 2–8 carbon atoms, or phenyl;    V is (CH2)m, O, S, or NR6;    R7 is NR6R6, OR6, J, N(R6)3+, or NR6(OR6);    M is NR6, O, S, N-[(C(R6)2)pNR6R6], or N-[(C(R6)2)p—OR6];    W is NR6, O, S, or is a bond;    Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and tetrahydropyran; wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R6; optionally mono- or di-substituted on carbon with hydroxy, —N(R6)2, or —OR6; optionally mono or di-substituted on carbon with the mono-valent radicals —(C(R6)2)sOR6 or —[(C(R6)2)sN(R6)2]; or optionally mono or di-substituted on a saturated carbon with divalent radicals ═O or —O(C(R6)2)sO—;    Ph is a phenyl ring optionally mono-, di- or tri-substituted with halogen, alkyl of 1–6 carbon atoms, trifluoromethyl, nitro, cyano, azido, halomethyl, carboxyl, alkoxycarbonyl, alkylthio, mercapto, mercaptomethyl, —N(R6)2, —OR6, —(C(R6)2)sOR6, —[(C(R6)2)sN(R6)2], or —(C(R6)2)kHet;    R6 is hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, cycloalkyl of 1–6 carbon atoms, alkanoyl of 2–7 carbon atoms, carbamoylalkyl of 2–7 carbon atoms, hydroxyalkyl of 1–6 carbon atoms, hydroxycycloalkyl of 3–6 carbon atoms, or carboxyalkyl of 2–7 carbon atoms; or    R6 is phenyl optionally mono-, di-, or tri-substituted with substituent(s) independently selected from halogen, alkoxy of 1–6 carbon atoms, trifluoromethyl, amino, alkylamino of 1–3 carbon atoms, dialkylamino of 2–6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2–7 carbon atoms, alkanoyloxymethyl of 2–7 carbon atoms, alkylthio of 1–6 carbon atoms, hydroxy, carboxyl, alkoxycarbonyl of 2–7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino; alkanoylamino of 1–6 carbon atoms or alkyl of 1–6 carbon atoms;    R8 and R9 are each, independently, —[(C(R6)2)rNR6R6], and —[(C(R6)2)r OR6];    J is independently hydrogen, chlorine, fluorine, or bromine;    g=1–6;    k=0–4;    p=2–4;    q=0–4;    r=1–4;    s=1–6;    or a pharmaceutically acceptable salt thereof;    provided that when
                at least one of the bonds between A and B or B and D must be a double bond, with the other being a single bond;        at least one of A, B, and D are not carbon;        only one of A, B, or D can be O or S;        when A, B, or D is O or S, the adjacent atoms must be carbon;            provided that when R5 is bound to a nitrogen atom, the resulting structures do not include —N—C—N— or —O—C—N— radicals; and when R5 is bound to an oxygen atom, the resulting structures do not include an —N—C—O— radical;    provided that when R6 is alkenyl of 2–7 carbon atoms or alkynyl of 2–7 carbon atoms, the alkenyl or alkynyl moieties are bound to a nitrogen or oxygen atom through a saturated carbon atom in the alkenyl or alkynyl chain;    provided that when V is NR6 and R7 is NR6R6, N(R6)3+, or NR6(OR6), then g=2–6;    provided that when M is O or S and R7 is OR6, then p=1–4;    provided that when V is NR6, O, S, then k=2–4;    provided that when V is O or S and M or W is O or S, then k=1–4    provided that when W is not a bond with Het bonded through a nitrogen atom then q=2–4; and    finally provided when W is a bond with Het bonded through a nitrogen atom and V is O or NR6 or S, then k=2–4.
The present invention also relates to a method for making compounds of formula 1 and methods of using the compounds of formula 1.